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Human effector/memory CD4 T cell subsets: deep TCR profiling.

ABSTRACT: Clonal fate of helper T cells is governed by early costimulatory signals but may also depend on the mode of TCR interaction with peptide-MHC on APCs. We investigate TCR repertoires of eight effector/memory CD4+ T-cell subsets (Th1, Th2, nonclassical Th2 (Th2a), Th17, Th1-17, Tfh, Treg, Th22), revealing subset-specific physicochemical and recombinational features reproducible across donors. At a threshold of 3 reads per UMI, the number of obtained UMI-labeled cDNA molecules per repertoire per sample ranged from 5,300 to 303,500, and the number of CDR3 clonotype variants at the nucleotide level per repertoire per sample ranged from 1,200 to 83,200. Deep unbiased TCR profiling allowed us to assess the natural level of in vivo CD4+ subsets plasticity. We observed a major clonal exchange between Th17/Th22/Th2/Th2a and the high stability of Treg and Tfh subsets. The latter two subsets also show higher repertoire publicity across donors. Tfh repertoire features reflect those of mature antibodies and indicate stringent selection of highly antigen-specific, low cross-reactive TCRs. We conclude that functional subsets are marked with non-random universal for donors and specific features of passed selection. In future TCR sequencing applications, subset-specific profiling could provide better insights of normal and pathological states of adaptive immunity compared to the classical approach when TCR profiling is performed on bulk T cells or after rough division into CD4 and CD8-enriched populations.

ORGANISM(S): Homo sapiens

PROVIDER: GSE158848 | GEO | 2020/10/01

REPOSITORIES: GEO

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Project description:Infiltrating T-lymphocytes from the peripheral blood into the central nervous system (CNS) play a dynamic role in the development of a neurological immune-mediated diseases. HAM/TSP is a chronic progressive inflammatory neurological disorder associated with human T-cell lymphotropic virus type I (HTLV-I) infection. In this chronic myelopathy, virus-infected circulating T-cells infiltrate the CNS and an immune response is initiated against the components of CNS. As the HTLV-I proviral load (PVL) has been used as the best clinical marker for patient diagnostic with HAM/TSP, we hypothesized there might be a signature on T-cell receptor (TCR) clonal repertoire in these patients, which could distinguish HAM/TSP patients from the healthy population, as well as from patients with a more heterogeneous CNS-reactive inflammatory disease as multiple sclerosis (MS). With this in mind, we applied an innovative unbiased molecular technique – unique molecular identifier (UMI) library-strategy to investigate with high accuracy the TCR clonal repertoire by high throughput sequencing (HTS) technology. cDNA-TCR β-chain libraries were sequenced from 2 million peripheral mononuclear cells (PBMCs) in 14 HAM/TSP patients, 34 MS patients and 20 healthy controls (HC). To address whether the clonal expansion correlates with the patient’s PVL level, analysis of longitudinal TCR repertoire was performed in 2 HAM/TSP patients. Over 5.6 million TCR sequences were generated per sample on HiSeq 2500 Illumina system and analyzed through the molecular identifier groups-based error correction pipeline (MiGEC). Bioinformatic analysis showed that clones with more than 8 reads had a lower coefficient of variation (CV) and then could be used with confidence to evaluate the TCR clonal expansion. While HAM/TSP patients showed the higher clonal T-cell expansion compared to MS and HC, increase of the TCR clonal expansion was inversely correlated with the diversity of TCR repertoire in all subject’s group. In addition, correlation of the PVL with TCR clonal expansion was observed in HAM/TSP patients at longitudinal time-points. Surprisingly, MS patients showed a higher diversity of TCR repertoire along with a very slight clonal T-cell expansion in comparison to either HAM/TSP patients or HC. Despite of the higher TCR clonal expansion in HAM/TSP patients, a non-shared or “private” TCR repertoire was observed in these patients. No clones that shared the same CDR3 amino acid sequences were seen in HC and MS patients. However, a cluster of related CDR3 amino acid sequences were observed for 18 out of 34 MS patients when evaluated by phylogenetic tree analysis. It suggestes that a TCR-repertoire signature might characterize patients with MS. Our findings suggest that even though a unique TCR-b repertoire shapes the immune response in patients with neurological immune-mediated disease, a relatedness on clonal T-cell repertoire exist in MS.

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Human effector/memory CD4 T cell subsets: deep TCR profiling.

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